Molekulare Ursachen einer seltenen Form stationärer Farbenblindheit

Tränkner, Dimitri

Dissertation / PhD Thesis/Book

Molekulare Ursachen einer seltenen Form stationärer Farbenblindheit

Tränkner, D. (Corresponding author)FZJ*

2002
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag Jülich

Jülich : Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag, Berichte des Forschungszentrums Jülich 4037, V, 128 p. (2002) = Köln, Univ., Diss., 2002

Please use a persistent id in citations: http://hdl.handle.net/2128/2567

Report No.: Juel-4037

Abstract: Genetic analysis of patients suffering from autosomal recessively inherited achromatopsia revealed candidate mutations that might cause the disease. Most of these mutations are positioned in the genes coding for the subunits CNGA3 and CNGB3 of the cyclic nucleotidegated (CNG) channel present in cone photoreceptors (WISSINGER et al., $\textit{Am. J. Hum. Genet.}$ 69: 722-737, 2001). Two siblings suffering from incomplete achromatopsia carry two mutated $\textit{CNGA3}$ alleles, respectively. One mutation leads to a substitution of Thr to Arg in the S2-S3- linker (A3$_{T224R}$), the other mutation leads to a substitution of Thr to Ser in the pore region (A3$_{T369S}$) of CNGA3. Psychophysical measurements revealed, that the cone photoreceptor system of the siblings is characterized by reduced sensitivity. Electroretinographic measurements indicate a perturbed synaptic transmission from cone photoreceptors to secondary neurons. Heterologous expression of the mutant channel subunits in HEK293 cells revealed that only A3$_{T369S}$ forms functional channels. Compared to the wildtype protein (A3), A3$_{T369S}$ displayed 1) increased single-channel conductance, 2) reduced apparent affinity of the pore for extracellular Ca$^{2+}$, 3) altered gating and 4) substantially reduced ligand sensitivity. Surprisingly, co-expression of the A3 or A3$_{T369S}$ with CNGB3 (B3) leads to channels with almost similar functional properties: conductance, gating behaviour and ligand sensitivity of A3/B3 and A3$_{T369S}$/B3 are indistinguishable. However, the apparent affinity for extracellular Ca$^{2+}$ remained smaller for A3$_{T369S}$B3. lt is plausible, that the changed Ca$^{2+}$ affinity is responsible for the diseased state of the achromatic siblings.

Note: Record converted from VDB: 12.11.2012
Note: Köln, Univ., Diss., 2002

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